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miR-21 regulates immunosuppression mediated by myeloid-derived suppressor cells by impairing RUNX1-YAP interaction in lung cancer

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) are known suppressors of antitumor immunity and contribute to immunosuppressive microenvironment during tumor development including lung cancer. Accumulating evidence shows microRNAs (miRNAs) affect tumor-expanded MDSC accumulation and function in...

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Autores principales: Meng, Guangping, Wei, Jinying, Wang, Yanjun, Qu, Danhua, Zhang, Jie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549228/
https://www.ncbi.nlm.nih.gov/pubmed/33061847
http://dx.doi.org/10.1186/s12935-020-01555-7
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author Meng, Guangping
Wei, Jinying
Wang, Yanjun
Qu, Danhua
Zhang, Jie
author_facet Meng, Guangping
Wei, Jinying
Wang, Yanjun
Qu, Danhua
Zhang, Jie
author_sort Meng, Guangping
collection PubMed
description BACKGROUND: Myeloid-derived suppressor cells (MDSCs) are known suppressors of antitumor immunity and contribute to immunosuppressive microenvironment during tumor development including lung cancer. Accumulating evidence shows microRNAs (miRNAs) affect tumor-expanded MDSC accumulation and function in tumor microenvironment and favor solid tumor growth. Herein, we aim to characterize the role of miR-21 in regulating the accumulation and activity of MDSCs in lung cancer. METHODS: The proportions of MDSCs, T helper cells (Th), and cytotoxic T lymphocytes (CTL) were evaluated by flow cytometric analyses of peripheral blood and tumor tissues collected from Lewis lung-cancer-bearing mice. T cell proliferation assay was performed in CD4+ or CD8+ T cells cocultured with MDSCs. MDSC apoptosis was examined by flow cytometric analysis. The levels of IL-10, TGF-β, and GM-CSF in mouse serum were determined by ELISA. miR-21 targeting RUNX1 and RUNX1 interaction with YAP were evaluated by RIP, dual-luciferase reporter gene, and ChIP assays. RESULTS: MiR-21 inhibition by its antagomir reduced the proportion of MDSCs, increased the proportion of Th and CTL in peripheral blood and tumor tissues of Lewis lung-cancer-bearing mice, protected Th and CTL from the suppression of MDSCs, increased apoptosis of MDSCs, but reduced IL-10, TGF-β and GM-CSF levels in mouse serum. RUNX1 could transcriptionally inhibit the YAP expression, whereas miR-21 targeting RUNX1 led to elevated YAP expression levels. Mechanistic investigation showed that miR-21 maintained MDSC accumulation in tumor microenvironment and promoted immunosuppressive ability of MDSCs in Lewis lung-cancer-bearing mice by down-regulating RUNX1and up-regulating YAP. CONCLUSIONS: Taken together, the study provides evidence that targeting miR-21 in MDSCs may be developed as an immunotherapeutic approach to combat lung cancer development.
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spelling pubmed-75492282020-10-13 miR-21 regulates immunosuppression mediated by myeloid-derived suppressor cells by impairing RUNX1-YAP interaction in lung cancer Meng, Guangping Wei, Jinying Wang, Yanjun Qu, Danhua Zhang, Jie Cancer Cell Int Primary Research BACKGROUND: Myeloid-derived suppressor cells (MDSCs) are known suppressors of antitumor immunity and contribute to immunosuppressive microenvironment during tumor development including lung cancer. Accumulating evidence shows microRNAs (miRNAs) affect tumor-expanded MDSC accumulation and function in tumor microenvironment and favor solid tumor growth. Herein, we aim to characterize the role of miR-21 in regulating the accumulation and activity of MDSCs in lung cancer. METHODS: The proportions of MDSCs, T helper cells (Th), and cytotoxic T lymphocytes (CTL) were evaluated by flow cytometric analyses of peripheral blood and tumor tissues collected from Lewis lung-cancer-bearing mice. T cell proliferation assay was performed in CD4+ or CD8+ T cells cocultured with MDSCs. MDSC apoptosis was examined by flow cytometric analysis. The levels of IL-10, TGF-β, and GM-CSF in mouse serum were determined by ELISA. miR-21 targeting RUNX1 and RUNX1 interaction with YAP were evaluated by RIP, dual-luciferase reporter gene, and ChIP assays. RESULTS: MiR-21 inhibition by its antagomir reduced the proportion of MDSCs, increased the proportion of Th and CTL in peripheral blood and tumor tissues of Lewis lung-cancer-bearing mice, protected Th and CTL from the suppression of MDSCs, increased apoptosis of MDSCs, but reduced IL-10, TGF-β and GM-CSF levels in mouse serum. RUNX1 could transcriptionally inhibit the YAP expression, whereas miR-21 targeting RUNX1 led to elevated YAP expression levels. Mechanistic investigation showed that miR-21 maintained MDSC accumulation in tumor microenvironment and promoted immunosuppressive ability of MDSCs in Lewis lung-cancer-bearing mice by down-regulating RUNX1and up-regulating YAP. CONCLUSIONS: Taken together, the study provides evidence that targeting miR-21 in MDSCs may be developed as an immunotherapeutic approach to combat lung cancer development. BioMed Central 2020-10-12 /pmc/articles/PMC7549228/ /pubmed/33061847 http://dx.doi.org/10.1186/s12935-020-01555-7 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Primary Research
Meng, Guangping
Wei, Jinying
Wang, Yanjun
Qu, Danhua
Zhang, Jie
miR-21 regulates immunosuppression mediated by myeloid-derived suppressor cells by impairing RUNX1-YAP interaction in lung cancer
title miR-21 regulates immunosuppression mediated by myeloid-derived suppressor cells by impairing RUNX1-YAP interaction in lung cancer
title_full miR-21 regulates immunosuppression mediated by myeloid-derived suppressor cells by impairing RUNX1-YAP interaction in lung cancer
title_fullStr miR-21 regulates immunosuppression mediated by myeloid-derived suppressor cells by impairing RUNX1-YAP interaction in lung cancer
title_full_unstemmed miR-21 regulates immunosuppression mediated by myeloid-derived suppressor cells by impairing RUNX1-YAP interaction in lung cancer
title_short miR-21 regulates immunosuppression mediated by myeloid-derived suppressor cells by impairing RUNX1-YAP interaction in lung cancer
title_sort mir-21 regulates immunosuppression mediated by myeloid-derived suppressor cells by impairing runx1-yap interaction in lung cancer
topic Primary Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549228/
https://www.ncbi.nlm.nih.gov/pubmed/33061847
http://dx.doi.org/10.1186/s12935-020-01555-7
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